Artemether-lumefantrine is the leading drug recommended by the World Health Organization (WHO) for the treatment of uncomplicated malaria caused by Plasmodium falciparum. High treatment efficacy, good tolerability, and an acceptable safety profile of artemether-lumefantrine have been established in non-pregnant adults and children. However, despite increasing use of the drug in pregnant women in many endemic countries following the WHO recommendation, knowledge on the pharmacokinetics, safety and efficacy of artemether-lumefantrine is extremely limited in the pregnant population, especially in those living with HIV who carry a significantly higher burden of malaria, in malaria-endemic African nations where the prevalence of HIV is consistently higher in the pregnant than the general population. It is not known whether the remarkable record of high efficacy and good safety of artemether- lumefantrine is sustained in this vulnerable population. Available data suggest that pregnancy- and HIV-related immune suppression and suboptimal pharmacokinetics secondary to pregnancy-induced acceleration in drug disposition may hamper the efficacy of artemether-lumefantrine. Members of the public health and research communities have also repeatedly expressed concern about potential interactions between antimalarial and antiretroviral drugs modifying antimalarial drug efficacy and safety in this population, since the use and availability of antiretroviral drugs in developing nations has doubled in the last 5 years, with the powerful push for universal access to antiretroviral treatment. The overall public health objective of this proposal is to determine if standard doses of artemether- lumefantrine are safe and efficacious in pregnant women who are taking nevirapine-based ART for the treatment of HIV. The primary research objective is to assess the efficacy of artemether-lumefantrine in the treatment of uncomplicated malaria in HIV-infected pregnant women in comparison with HIV-negative pregnant and HIV-infected non-pregnant women. The secondary objectives are to assess safety, and to evaluate the relative contributions of pharmacokinetics (which may be modified by pregnancy-related changes and/or interaction with nevirapine), drug resistance, and acquired immunity (which may be modified by pregnancy- and HIV-related immunosuppression) in the treatment outcomes. In close collaboration with our colleagues in Mali and Burkina Faso, we have designed a clinical trial to compare the treatment efficacy and safety of artemether-lumefantrine in three cohorts of (HIV-infected pregnant, HIV-negative pregnant, and HIV-infected non-pregnant women). The pharmacokinetics of artemether and lumefantrine, and molecular markers known or suspected to be associated with falciparum drug resistance will be evaluated in association with the treatment outcomes. Samples will be preserved to assess the role of impaired immunity in therapeutic efficacy, under separate funding. PUBLIC HEALTH RELEVANCE (provided by applicant): The proposed clinical trial will focus on pregnant women living with HIV who are also at risk of malaria. Pregnant women, with or without HIV, are typically excluded from clinical drug trials for fear of harm to the fetus, resulting in an almost complete lack of scientific evidence to guide drug treatment in pregnancy, a state in which drug safety, pharmacokinetics and efficacy may be affected. Study findings will be of immediate and direct relevance for public health professionals and policy makers in West Africa where malaria-HIV co- infection is prevalent, by providing clinical evidence to determine whether the standard malaria treatment with artemether-lumefantrine is safe and effective in this specific population, and adequate pharmacokinetic data to carefully develop a pharmacokinetic-based appropriate dosing regimen to optimize clinical efficacy and safety if necessary.